Protein kinases are enzymes that play a key role in cell signal transduction. They are involved in physiological processes such as cell proliferation, mitosis, differentiation, cell invasion and mobility, and apoptosis, for example.
Deregulation of the physiological mechanisms controlled by protein kinases is central to the appearance and development of many pathologies, notably including cancers. It is of particular note that many oncogenes and proto-oncogenes correspond to protein kinases.
Consequently, these enzymes are seen to play an important role during the various stages of tumor development and thus they constitute important pharmaceutical targets for cancer treatments.
Tyrosine kinase receptors (TKRs) form a particular class of protein kinases among which, among others, mention may be made of ALK, EGFR, Her2, PDGFR, Kit, VEGFR, IGFR, FGFR, Trk, Axl, Mer, Met, Ron and Ret. In this subfamily, ALK is regarded as a particularly relevant target because it is genetically modified in certain tumor pathologies and thus acquires an oncogenic nature. More precisely, chromosomal translocations leading to the production of fused protein kinases (ALK-X) which are then constitutively activated cause the development of certain cancers. ALK in oncogenic form is expressed by various tumor pathologies of different histological types. These pathologies are thus ALK-dependent. ALK in oncogenic form exists only in tumor cells and is not expressed by normal cells. For this reason, this protein kinase provides the opportunity to specifically target ALK-dependent tumor tissues while saving healthy tissues from significant toxic effects (Ott G. R. et al., Anticancer Agents Med. Chem., 2010, 10(3), 236-49).
Several cases of chromosomal translocations involving ALK, related to cancer pathologies, have already been documented. For example, the fusion protein NPM-ALK is associated with anaplastic large-cell lymphoma (ALCL) for which an optimal treatment remains to be developed. Similarly, the fusion protein EML4-ALK is associated with tumor development in a subpopulation of patients suffering from non-small cell lung cancer. Mutated forms of ALK have also been observed in neuroblastoma.
c-Src is also a protein kinase whose activation state proved to be negatively correlated with the survival of patients suffering from various forms of cancer, including non-small cell lung cancer (Byers L. A. et al., Clin. Cancer Res. 2009, 15(22), 6852-6861).
For this reason, and because of its involvement in many key mechanisms such as cell cycle progression, adhesion, proliferation, migration and control of apoptosis, this protein is also regarded as a target of interest in oncology.
It has been shown in particular that the inhibition of this target, by both biochemical and pharmacological means, induced effects such as a reduction in cell proliferation, a stopping of the mitotic cycle and a slowing of tumor growth in vivo. In the particular case of non-small cell lung cancer, the inhibition of c-Src by an inhibitor (dasatinib) led to the observation, in vitro, of inhibition of the migration and the invasion of the cells concerned.
Nevertheless, in terms of the control of tumor cell proliferation, it has been proposed that c-Src inhibition alone only induces a partial and/or transitory pharmacological response.
Consequently, there continues to be a need for inhibitors with a composite mode of action that are capable of intervening at several targets, in particular at several targets of the same signaling pathway, proposed as being more effective, with an improved therapeutic index and less likely to give rise to phenomena of compensation, resistance or therapeutic escape.